Serotonin and norepinephrine reuptake inhibitors and uses thereof

ABSTRACT

Selective dual serotonin and norepinephrine reuptake inhibitors are provided. These compounds have a lower side-effect profile and are useful in compositions and products for use in treatment of a variety of conditions including depression, fibromyalgia, anxiety, panic disorder, agorophobia, post traumatic stress disorder, premenstrual dysphoric disorder, attention deficit disorder, obsessive compulsive disorder, social anxiety disorder, generalized anxiety disorder, autism, schizophrenia, obesity, anorexia nervosa, bulimia nervosa, Gilles de la Tourette Syndrome, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction, borderline personality disorder, fibromyalgia syndrome, diabetic neuropathic pain, chronic fatigue syndrome, pain, Shy Drager syndrome, Raynaud&#39;s syndrome, Parkinson&#39;s Disease, and epilepsy.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 USC 119(e) of U.S. PatentApplication No. 60/699,737, filed Jul. 15, 2005.

BACKGROUND OF THE INVENTION

The market for neuroscience and women's health drugs has been movingtowards the use of dual serotonin and norepinephrine reuptake inhibitors(SNRI) for first line treatment of various indications, as evidenced bythe recent development of SNRI's such as Venlafaxine and Duloxetine.This contrasts with the traditional use of selective serotonin reuptakeinhibitors (SSRI). Although the side-effect profile of SSRI's and SNRI'sare less severe as compared to older, tricyclic antidepressantscompounds, there are still some undesirable side effects related to theselectivity or other neuronal receptor binding (muscarinic, histamineand alpha-adrenergic, etc.) of these SSNI's and SNRI's. Binding to thesereceptors can lead to side effects such as, dry mouth, drowsiness,appetitite stimulation and some cardiovascular risks.

The higher norepinephrine (NE) activity of SNRI's has also beenimplicated in a number of side effects and therefore limits theirapplication. For example, the currently available SNRI's have limitedapplication for the treatment of irritable bowel syndrome (IBS) becauseof the constipation side effect associated with higher NE activity.Another potential side effect of SNRI's is that at higher dosages thereis a modest increase in diastolic blood pressure and this side effect isassociated with higher NE activity. Further, potential overdosesituations have been associated with excess adrenergic stimulation,seizures, arrhythmias, bradycardia, hypertension, hypotension and death.

What are needed are alternative compositions for treating conditionsassociated with serotonin and norepinephrine imbalances, by allowingserotonin and or norepinephrine re-uptake inhibition for efficacy withlower post synaptic receptor binding for reduced side-effects [(H. Hall,et al., Acta pharmacol et. toxicol. 1984, 54, 379-384)].

SUMMARY OF THE INVENTION

The present invention provides a compound with dual serotonin andnorepinephrine reuptake inhibitor activity with lower undesirableside-effects.

In one aspect, the invention provides a compound of the structure:

wherein R²=H, C₁-C₆ alkyl, substituted C₁-C₆alkyl, CF₃, CN, halogen, OH;

or a prodrug or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of the invention and pharmaceutically acceptablecarrier.

In still another aspect, the invention provides a method of using thecompound of the invention for treating irritable bowel syndrome,premature ejaculation and urinary incontinence in a subject in needthereof.

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of the invention and pharmaceutically acceptablecarrier.

Still other aspects and advantages of the invention will be apparentfrom the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a new class of compounds which has thestructure:

wherein R²=H, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, CF₃, CN, halogen,OH;

or a prodrug or a pharmaceutically acceptable salt thereof.

Compounds and formulations described herein are anticipated to reduceone or more of the undesirable side-effects of SNRI's, includingconstipation, hypertension, and the histamine-related side-effects.Compounds described herein are also predicted to have low norepinephrinereuptake inhibition activity (NE), as compared to existing SNRI's. Thisattribute is very attractive for SNRI indications, e.g., depression, forpatients that have cardiovascular risks related to hypertension. Thecompounds of the invention will have activity on serotonin andnorepinephrine neurotransmitters in the brain making it ideal foranti-depression therapy and other related neurological indications.

In one embodiment, the compounds may contain one or more asymmetriccarbon atoms and some of the compounds may contain one or moreasymmetric (chiral) centers and may thus give rise to optical isomersand diastereomers. While shown without respect to stereochemistry in thestructure above, in one embodiment, the compound contains a chiralcenter. However, this molecule can exist in a form of R and S isomers aswell as the racemic mixture. Thus, compounds and compositions describedherein may include such optical isomers and disastereomers; as well asthe racemic and resolved, enantiomerically pure stereoisomers; as wellas other mixtures of the R and S stereoisomers, and pharmaceuticallyacceptable salts, hydrates, and prodrugs thereof.

The term “alkyl” is used herein to refer to both straight- andbranched-chain saturated aliphatic hydrocarbon groups, generally of 1,2, 3, 4, 5, 6, 7 or 8 carbon atoms in length, unless otherwisespecified. The term “lower alkyl” is used to refer to alkyl chains of 1,2, 3, or 4 carbons in length. The terms “substituted alkyl” refers toalkyl as just described having from one to three substituents selectedfrom the group including halogen, CN, OH, NO₂, amino, aryl,heterocyclic, substituted aryl, substituted heterocyclic, alkoxy,aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino,arylthio. These substituents may be attached to any carbon of alkylgroup provided that the attachment constitutes a stable chemical moiety.

The term “halogen” refers to Cl, Br, F, or I.

The term “aryl” is used herein to refer to a carbocyclic aromaticsystem, which may be a single ring, or multiple aromatic rings fused orlinked together as such that at least one part of the fused or linkedrings forms the conjugated aromatic system. The aryl groups include, butare not limited to, phenyl, naphthyl, biphenyl, anthryl,tetrahydronaphthyl, and phenanthryl.

The term “substituted aryl” refers to aryl as just defined having one,two, three or four substituents from the group including halogen, CN,OH, NO₂, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy,substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, andarylthio.

The term “heterocyclic” is used herein to describe a stable 4-, 5-, 6-or 7-membered monocyclic or a stable multicyclic heterocyclic ring whichis saturated, partially unsaturated, or unsaturated, and which consistsof carbon atoms and from one to four heteroatoms selected from the groupincluding N, O, and S atoms. At least one carbon atom may be C═O. The Nand S atoms may be oxidized. The heterocyclic ring also includes anymulticyclic ring in which any of above defined heterocyclic rings isfused to an aryl ring. A multicyclic ring may be 2 or 3 monocyclic ringsof 4- to 7-membered rings as described above. The heterocyclic ring maybe attached at any heteroatom or carbon atom provided the resultantstructure is chemically stable. Such heterocyclic groups include, forexample, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl,azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl,thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl,thiamorpholinyl sulfoxide, and isoquinolinyl

The term “substituted heterocyclic” is used herein to describe theheterocyclic just defined having one to four substituents selected fromthe group which includes halogen, CN, OH, NO₂, amino, alkyl, substitutedalkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy,aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino,or arylthio.

The term “alkoxy” is used herein to refer to the OR group, where R isalkyl or substituted alkyl. The term “aryloxy” is used herein to referto the OR group, where R is aryl or substituted aryl. The term“alkylcarbonyl” is used herein to refer to the RCO group, where R isalkyl or substituted alkyl. The term “alkylcarboxy” is used herein torefer to the COOR group, where R is alkyl or substituted alkyl. The term“aminoalkyl” refers to both secondary and tertiary amines wherein thealkyl or substituted alkyl groups, containing one to eight carbon atoms,which may be either same or different and the point of attachment is onthe nitrogen atom.

The compounds can be used in the form of salts derived frompharmaceutically or physiologically acceptable acids or bases. Thesesalts include, but are not limited to, the following salts with organicand inorganic acids such as acetic, lactic, citric, tartaric, succinic,fumaric, maleic, malonic, mandelic, mallic, hydrochloric, hydrobromic,phosphoric, nitric, sulfuric, methanesulfonic, toluenesulfonic andsimilarly known acceptable acids, and mixtures thereof. Other saltsinclude salts with alkali metals or alkaline earth metals, such assodium (e.g., sodium hydroxide), potassium (e.g., potassium hydroxide),calcium or magnesium.

These salts, as well as other compounds, may be in the form of esters,carbamates and other conventional “pro-drug” forms, which, whenadministered in such form, convert to the active moiety in vivo. In oneembodiment, the prodrugs are esters. See, e.g., B. Testa and J.Caldwell, “Prodrugs Revisited: The “Ad Hoc” Approach as a Complement toLigand Design”, Medicinal Research Reviews, 16(3):233-241, ed., JohnWiley & Sons (1996).

In one embodiment, the invention provides4-[2-Dimethylamino-1-(4-hydroxy-phenyl)-ethyl]piperidin-4-ol or apharmaceutically acceptable salt, or prodrug thereof. The free base ofthis compound has the structure:

4-[2-Dimethylamino-1-(4-hydroxy-phenyl)-ethyl]-piperidin-4-ol

In another embodiment, the invention provides4-[2-Dimethylamino-1-(4-hydroxy-phenyl)-ethyl]-1-methyl-piperidin-4-ol,or a pharmaceutically acceptable salt, or prodrug thereof. The free baseof this compound has the structure:

4-[2-Dimethylamino-1-(4-hydroxy-phenyl)-ethyl]-1-methyl-piperidin-4-ol

In still another embodiment, the invention provides4-[2-Dimethylamino-1-(4-hydroxy-phenyl)-ethyl]-1-ethyl-piperidin-4-ol,or a pharmaceutically acceptable salt, or prodrug thereof. The free baseof this compound has the structure:

4-[2-Dimethylamino-1-(4-hydroxy-phenyl)-ethyl]-1-ethyl-piperidin-4-ol

In yet another embodiment, the invention provides4-[2-Dimethylamino-1-(4-hydroxy-phenyl)-ethyl]-1-propyl-piperidin-4-ol,or a pharmaceutically acceptable salt, or prodrug thereof. The free baseof this compound has the structure:

4-[2-Dimethylamino-1-(4-hydroxy-phenyl)-ethyl]-1-propyl-piperidin-4-ol

In a further embodiment, the invention provides4-[2-Dimethylamino-1-(4-hydroxy-phenyl)-ethyl]-1-isopropyl-piperidin-4-ol,or a pharmaceutically acceptable salt, or prodrug thereof. The free baseof this compound has the structure:

4-[2-Dimethylamino-1-(4-hydroxy-phenyl)-ethyl]-1-isopropyl-piperidin-4-olSynthesis

The compounds described herein can be prepared using the methodsdescribed below, together with synthetic methods known in the syntheticorganic arts or variations of these methods by one skilled in the art.[See, generally, Comprehensive Organic Synthesis, “Selectivity, Strategy& Efficiency in Modern Organic Chemistry”, ed., I. Fleming, PergamonPress, New York (1991); Comprehensive Organic Chemistry, “The Synthesisand Reactions of Organic Compounds”, ed. J. F. Stoddard, Pergamon Press,New York (1979)]. Suitable methods include, but are not limited to,those outlined below.

In another embodiment, a compound of structure A can be prepared asdescribed below:

wherein X is N, Y is C, R² is selected from H, OH, halogen, CF₃, phenyl,SCH₃, NHCH₃, C₁-C₆ alkyl, substituted C₁-C₆alkyl.

This method involves the step of reacting a2-(4-hydroxy-phenol)-dimethylacetamide with a benzyl halide to afford a2-(4-benzyloxy-phenyl)-dimethylacetamide. The2-(4-hydroxy-phenol)-dialkylacetamide may be in a solution comprisingdimethylformamide. Further, the solution can be treated with potassiumcarbonate prior to reaction with the benzyl halide.

To prepare the compound of structure A, the2-(4-benzyloxy-phenyl)-dimethylacetamide is reacted with a compoundhaving the structure:

in a solution (e.g., containing THF) with a suitable base. In thisstructure, X is N, Y is a C, R² is selected from H, OH, halogen, phenyl,CF₃, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl. Examples of suitablebases include, e.g., lithium diisopropylamide and isopropyl magnesiumbromide. In one embodiment, this compound is selected from the groupconsisting of pyran-4-one and phenyl-piperidine-4-one. The resultingproduct is reduced (e.g., using LiAlH₄) to provide the correspondingdimethylamine and the benzyl ether is hydrogenated to remove the benzylgroup and afford a compound of structure A.

Advantageously, it has been found that the process is highly selectivefor the cis-compounds, leading to a high yield and good crystallinity.Without wishing to be bound by theory, it is believed that the LAHreaction plays a significant role in this specificity.

In one embodiment, the method of synthesizing the compounds of theinvention provides a compound having a configuration is greater than 50%cis diastereomer. In another embodiment, the method of synthesizing thecompounds of the invention provides a compound having the configurationwhich is greater than 95% cis diastereomer. In another embodiment, itmay be desirable to substitute sodium borohydride for the LAH.

4-(Dimethylcarbamoylmethyl)phenol in dimethylformamide (DMF) is treatedwith K₂CO₃ followed by benzyl bromide. The benzyl bromide protectinggroup is particularly well suited for use in the method of synthesizingthe compounds of the invention because of its ease of removal during thefinal step. However, other protecting groups may be substituted.

The mixture is stirred at room temperature followed by heating at 60° C.for 1 hour. The mixture is concentrated to remove DMF, diluted withEtOAc and washed with water. Dry MgSO₄ is added, the mixture filteredand concentrated to low volume. Hexane is added to precipitate the ketalintermediate product. Solids are collected via filtration and dryed.

A solution of a piperidine ketal with the appropriate protecting groupand substituents in 100 mL THF/50 mL MeOH is treated with acid (e.g.,HCl), then stirred at room temperature. In one embodiment, theprotecting group is a phenyl ring.

The appropriate protecting group and/or substituents are added to theketal either before the LDA reaction or after the LDA reaction usingconventional methods. The reaction is quenched with saturated K₂CO₃,extracted with EtOAc and concentrated to an oil. Product is crystallizedfrom hot EtOAc/hexanes to provide the ketone intermediate.

A solution of the ketone in THF was added to a suspension of lithiumaluminum hydride (LAH) pellets in THF at −78° C. The mixture is warmedto room temperature and stirred for at least 3 hours. The reaction isquenched with MeOH followed by 10% NaOH and stirred for at least 3hours. The solid are removed by filtration, followed by a wash (e.g.,with THF), and concentrated to give a solid. The resulting solid isrecrystallized from EtOAc/hexanes to provide the corresponding benzylether.

Advantageously, it has been found that this process is highly selectivefor the cis-compounds, leading to a high yield and good crystallinity.Without wishing to be bound by theory, it is believed that the LAHreaction plays a significant role in this specificity. In oneembodiment, the method of synthesizing the compounds of the inventionprovides a compound having a configuration is greater than 50% cisdiastereomer. In another embodiment, this process provides a compoundhaving the configuration which is greater than 95% cis diastereomer. Inanother embodiment, it may be desirable to substitute sodium borohydridefor the LAH.

A mixture of the benzyl ether and Pd/C in 100 mL of ethanol arehydrogenated under pressure overnight. The solid is purified byfiltration followed by an ethanol wash. Solid is concentrated andcrystallized from EtOAc/hexane to give the final product.

Salts may be formed by contacting stoichiometric amounts of the acidwith the free base. Alternatively, the acid may be used in excess,usually no more than 1.5 equivalents. In one embodiment, the base or theacid are in solution, or both are in solution.

The crystalline salt may be prepared by directly crystallizing from asolvent. Improved yield may be obtained by evaporation of some or all ofthe solvent or by crystallization at elevated temperatures followed bycontrolled cooling, preferably in stages. Careful control ofprecipitation temperature and seeding may be used to improve thereproducibility of the production process and the particle sizedistribution and form of the product.

Use of the Compounds of Invention

In one embodiment, the invention provides compounds with a differentratio of serotonin reuptake inhibition to norepinephrine reuptakeinhibition than the currently available SNRI's. This attribute is veryattractive for indications like Irritable Bowel Syndrome (IBS) where thehigher NE activity of SNRI's limits the application because ofconstipation and other gastrointestinal side effects. This lower NEactivity is also attractive for patients that have cardiovascular risksrelated to the side effect of hypertension. It also has an applicationin dealing with urinary incontinence.

The compositions of the present invention can be used to treat orprevent central nervous system disorders including, but not limited to,depression (including but not limited to, major depressive disorder,bipolar disorder and dysthymia), anxiety, fibromyalgia, anxiety, panicdisorder, agorophobia, post traumatic stress disorder, premenstrualdysphoric disorder (also known as premenstrual syndrome), attentiondeficit disorder (with and without hyperactivity), obsessive compulsivedisorder (including trichotillomania), social anxiety disorder,generalized anxiety disorder, autism, schizophrenia, obesity, anorexianervosa, bulimia nervosa, Gilles de la Tourette Syndrome, vasomotorflushing, cocaine and alcohol addiction, sexual dysfunction, (includingpremature ejaculation), borderline personality disorder, chronic fatiguesyndrome, incontinence (including fecal incontinence, overflowincontinence, passive incontinence, reflex incontinence, stress urinaryincontinence, urge incontinence, urinary exertional incontinence andurinary incontinence), pain (including but not limited to migraine,chronic back pain, phantom limb pain, central pain, neuropathic painsuch as diabetic neuropathy, and postherpetic neuropathy), Shy Dragersyndrome, Raynaud's syndrome, Parkinson's Disease, epilepsy, and others.Compounds and compositions described herein can also be used forpreventing relapse or recurrence of depression; to treat cognitiveimpairment; for the inducement of cognitive enhancement in patientsuffering from senile dementia, Alzheimer's disease, memory loss,amnesia and amnesia syndrome; and in regimens for cessation of smokingor other tobacco uses. Additionally, compounds and compositions of thepresent invention can be used for treating hypothalamic amenorrhea indepressed and non-depressed human females.

An effective amount of the composition of the invention is an amountsufficient to prevent, inhibit, or alleviate one or more symptoms of theaforementioned conditions. The dosage amount useful to treat, prevent,inhibit or alleviate each of the aforementioned conditions will varywith the severity of the condition to be treated and the route ofadministration. The dose, and dose frequency will also vary according toage, body weight, response and past medical history of the individualhuman patient. In generally the recommended daily dose range for theconditions described herein lie within the range of 10 mg to about 1000mg per day, or within the range of about 15 mg to about 350 mg/day orfrom about 15 mg to about 140 mg/day. In other embodiments of theinvention, the dosage will range from about 30 mg to about 90 mg/day.Dosage is described in terms of the free base and is adjustedaccordingly for the succinate salt. In managing the patient, the therapyis generally initiated at a lower dose and increased if necessary.Dosages for non-human patients can be adjusted accordingly by oneskilled in the art.

A compound of the invention may also be provided in combination withother active agents including, e.g., venlafaxine. The dosage ofvenlafaxine is about 75 mg to about 350 mg/day or about 75 mg to about225 mg/day. In another embodiment, the dosage of venlafaxine is about 75mg to about 150 mg/day. Venlafaxine or another active agent delivered ina regimen with the composition of the invention may be formulatedtogether with the composition of the invention, or delivered separately.

Any suitable route of administration can be employed for providing thepatient with an effective amount of a compound of the invention. Forexample, oral, mucosal (e.g., nasal, sublingual, buccal, rectal orvaginal), parental (e.g. intravenous or intramuscular), transdermal, andsubcutaneous routes can be employed. Preferred routes of administrationinclude oral, transdermal and mucosal.

A compound of the invention can be combined with a pharmaceuticalcarrier or excipient (e.g., pharmaceutically acceptable carriers andexcipients) according to conventional pharmaceutical compoundingtechnique to form a pharmaceutical composition or dosage form. Suitablepharmaceutically acceptable carriers and excipients include, but are notlimited to, those described in Remington's, The Science and Practice ofPharmacy, (Gennaro, A R, ed., 19th edition, 1995, Mack Pub. Co.), whichis herein incorporated by reference. The phrase “pharmaceuticallyacceptable” refers to additives or compositions that are physiologicallytolerable and do not typically produce an allergic or similar untowardreaction, such as gastric upset, dizziness and the like, whenadministered to an animal, such as a mammal (e.g., a human).

Compositions

In one embodiment, the composition of the invention is an immediaterelease formulation. In another embodiment, the composition of theinvention is a sustained release formulation. Illustrative formulationsare described herein. However, the invention is not so limited.

Still other suitable embodiments of the invention will be readilyapparent to one of skill in the art given the information providedherein. For example, in addition to providing dosing units suitable fororal administration such as tablets, capsules and caplets, the inventionprovides dosing units suitable for parenteral administration,transdermal or mucosal administration.

Oral solid pharmaceutical compositions may include, but are not limitedto starches, sugars, microcrystalline cellulose, diluents, granulatingagents, lubricants, binders and disintegrating agents. In oneembodiment, the pharmaceutical composition and dosage form may alsoinclude other active components.

In one embodiment, the active component(s) are prepared in the form of atablet or tablet-in-capsule. For example, a compound of the invention ismixed with suitable excipients to form a granulation. In one embodiment,the granulation is formed using a roller compactor. In anotherembodiment, the granulation is formed using a high shear granulator.However, other methods known to those of skill in the art, including,e.g., a low shear granulator, a blender, etc, can be utilized to preparesuitable granulations. The granulation is then compressed usingconventional methods to form a tablet.

This tablet may be provided with additional layers, optionally,containing additional layers with active components, or other layers asmay be desired for enteric coating, seal coating, separation betweenlayers, or the like. In one embodiment, the tablet core contains oneactive component and a second active component is provided in a coatinglayer.

Optionally, a final seal coat is applied over the tablet. Suitably, thisfinal seal coat is composed of hydroxypropylmethylcellulose (HPMC) andwater, upon drying, is less than about 1 wt % of the total, coatedtablet. Optionally, talc is utilized as a final step prior to fillingthe multi-layer tablets into a suitable packaging unit.

Alternatively or additionally, the tablet may be loaded into a capsule.

In another aspect, the invention provides a capsule containing theactive component. Such capsules are produced using techniques known tothose of skill in the art.

In one embodiment, the invention provides a formulation containing acore of one or more of the compounds of the invention and one or morepharmaceutically acceptable excipients, e.g., diluents, binders,fillers, glidants, anti-adherents, a pH adjuster and/or an adjuvant. Thecore contains about 3% w/w to about 70% w/w active compound(s). In otherembodiments, the compound can range from about 5% w/w to about 60% w/w,from about 10% w/w to about 50% w/w, from about 20% w/w to about 40%w/w, or from about 25% w/w to about 35% w/w, about 30% w/w to about 45%w/w, or about 32% to about 44% w/w, based upon 100% weight of theuncoated dosage form. The core may be in a sustained release formulationor other suitable cores as are described in greater detail below may beselected. In one embodiment, a delay release coat and/or an enteric coatare provided over the core.

Suitably, the total amount of diluent, binders, fillers, glidants,anti-adherents, and adjuvants present in the core is an amount of about30% w/w to about 97% w/w of the core, or about 25 wt % to about 80 wt %of the core. For example, when present, a binder, diluent and/or fillercan each be present in an amount of about 15% w/w to about 80% w/w, orabout 20% w/w to about 70% w/w, or about 25% w/w to about 45% w/w, orabout 30% w/w to about 42% w/w of the uncoated dosage form. The totalamount of a pH adjuster in the formulation can range from about 0.1% w/wto about 10% w/w of the core, or about 1% w/w to about 8% w/w, or about3% w/w to about 7% w/w. However, these percentages can be adjusted asneeded or desired by one of skill in the art.

The binder may be selected from among known binders, including, e.g.,cellulose, and povidone, among others. In one embodiment, the binder isselected from among microcrystalline cellulose, crospovidone, andmixtures thereof.

Suitable pH adjusters include, e.g., sodium carbonate, sodiumbicarbonate, potassium carbonate, lithium carbonate, among others. Stillother suitable components will be readily apparent to one of skill inthe art.

In one embodiment, the compound(s) of the invention is in a sustainedrelease formulation which contains rate-controlling components.Typically, such rate controlling components are rate controllingpolymers selected from among hydrophilic polymers and inert plasticizedpolymers. Suitable rate controlling hydrophilic polymers include,without limitation, polyvinyl alcohol (PVA), hypomellose and mixturesthereof. Examples of suitable insoluble or inert “plastic” polymersinclude, without limitation, one or more polymethacrylates (i.e.,Eudragit® polymer). Other suitable rate-controlling polymer materialsinclude, e.g., hydroxyalkyl celluloses, poly(ethylene) oxides, alkylcelluloses, carboxymethyl celluloses, hydrophilic cellulose derivatives,and polyethylene glycol.

In one embodiment, a formulation of the invention contains about 5% w/wto about 75% w/w microcrystalline cellulose (MCC), about 10% w/w toabout 70% w/w MCC, about 20% w/w to about 60% w/w, about 25 wt % toabout 30 wt %, or about 30% w/w to about 50% w/w, based on the weight ofthe uncoated dosage unit.

In one embodiment, the core is uncoated. These cores can be placed intoa suitable capsule shell or compressed into tablets, using techniquesknow to those of skill in the art. Suitably, the results capsule shellor compressed tablets contain 10 mg to 400 mg of active compound.

In other embodiments, the formulation can contain one or more coatingsover the core. In still other embodiments, the formulation consists of apellet core and non-functional seal coating and a functional secondcoating.

In one embodiment, an initial seal coat can be applied directly to thecore. Although the components of this seal coat can be modified by oneof skill in the art, the seal coat may be selected from among suitablepolymers such as hydroxypropyl methylcellulose (HPMC), ethylcellulose,polyvinyl alcohol, and combinations thereof, optionally containingplasticizers and other desirable components. A particularly suitableseal coat contains HPMC. For example, a suitable seal coat can beapplied as a HPMC solution at a concentration of about 3% w/w to 25%w/w, and preferably 5% w/w to about 7.5% w/w. The initial seal coat canbe applied on a fluid bed coater, e.g., by spraying. In one embodiment,an Aeromatic Strea™ fluid bed apparatus can be fitted with a Wurstercolumn and bottom spray nozzle system. Approximately 200 grams of thedried pellet cores are charged into the unit. The Opadry® Clear sealcoat is applied with an inlet temperature of approximately 50° C. to 60°C., a coating solution spray rate of 5 to 10 grams/minute, atomizationpressure of 1 to 2 bar. Upon drying, under suitable conditions, theinitial seal coat is in the range of about 1% w/w to about 3% w/w, orabout 2% w/w, of the uncoated core. In another embodiment, acommercially available seal coat containing HPMC, among other inertcomponents, is utilized. One such commercially available seal coat isOpadry® Clear (Colorcon, Inc.).

In one embodiment, the oral dosage unit contains a further release or“delay” coating layer. This release coating layer may be applied over aninitial seal coat or directly over a core. In one embodiment, therelease coat contains an ethylcellulose-based product and hypomellose.An example of one suitable ethylcellulose-based product is an aqueousethylcellulose dispersion (25% solids). One such product is commerciallyavailable as Surelease® product (Colorcon, Inc.). In one embodiment, asolution of an aqueous ethylcellulose (25% solids) dispersion of about3% w/w to about 25% w/w, and preferably about 3% to about 7%, or about5% w/w, is applied to the core. Optionally, hypomellose, e.g., in anamount of about 5 to 15% by weight, and preferably, about 10% by weight,is mixed with the ethylcellulose dispersion, to form the coat solution.Thus, such the ethylcellulose may be about 85% to about 95%, by weight,or in embodiment, about 90% by weight, of the coat solution. Upon dryingunder suitable conditions, the total release coat is in the range ofabout 2% to about 5%, or about 3% to about 4% w/w of the uncoated orinitially-coated core.

An enteric coat (rate-controlling film) may be applied to themultiparticulates and may include, but is not limited topolymethacrylates, hypomellose, and ethylcellulose, or a combinationthereof. The modified release multiparticulate formulation can containfrom about 3% w/w to about 70% w/w of active compound or a combinationthereof, and from about 5% w/w to about 75% w/w microcrystallinecellulose, based on the weight of an uncoated dosage form.

In one embodiment, the enteric coat contains a product which is acopolymer of methacrylic acid and methacrylates, such as thecommercially available Eudragit® L 30 K55 (Röhm GmbH & Co. KG).Suitably, this enteric coat is applied such that it coats themultiparticulate in an amount of about 15 to 45% w/w, or about 20% w/wto about 30% w/w, or about 25% w/w to 30% w/w of the uncoated orinitially-coated multiparticulate. In one embodiment, the enteric coatis composed of a Eudragit® L30D-55 copolymer (Röhm GmbH & Co. KG), talc,triethyl citrate, and water. More particularly, the enteric coating maycontain about 30% w/w of a 30 wt % dispersion of Eudragit® L 30 D55coating; about 15% w/w talc, about 3% triethyl citrate; a pH adjustersuch as sodium hydroxide and water.

In another embodiment, the enteric coat contains an ethylcellulose-basedproduct, such as the commercially available Surelease® aqueousethylcellulose dispersion (25% solids) product (Colorcon, Inc.). In oneembodiment, a solution of Surelease® dispersion of about 3% w/w to about25% w/w, and preferably about 3% to about 7%, or about 5% w/w, isapplied to the multiparticulate. Upon drying under suitable conditions,the enteric coat is in the range of about 2% to about 5%, or about 3% toabout 4% w/w of the uncoated or initially-coated core.

The enteric coat can be applied directly to the uncoated core, i.e., theuncoated core, or may be applied over an initial seal coat. The entericcoat, as described above, is typically applied on a fluid bed coater. Inone embodiment, Surelease® aqueous ethylcellulose dispersion (25%solids) is applied in a similar fashion as the seal coat. After theethylcellulose coat is applied, the core is dried for an additional 5 to10 minutes.

In one embodiment, a final seal coat is applied over the enteric coatand, optionally, talc is utilized as a final step prior to filling theformulations into a suitable packaging unit. Suitably, this final sealcoat is composed of HPMC and water, upon drying, is less than about 1 wt% of the total, coated oral dosage unit.

Kits

In another embodiment, the present invention provides productscontaining the compounds and compositions of the invention.

In one embodiment, the compositions are packaged for use by the patientor his caregiver. For example, the compositions can be packaged in afoil or other suitable package and is suitable for mixing into a foodproduct (e.g., applesauce or the like) or into a drink for consumptionby the patient.

In another embodiment, the compositions are suspended in aphysiologically compatible suspending liquid. For oral liquidpharmaceutical compositions, pharmaceutical carriers and excipients caninclude, but are not limited to water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents, and the like.

In yet another embodiment, the compositions are filled in capsules,caplets or the like for oral delivery.

In another embodiment, the present invention provides for the use ofcompositions of the invention in the preparation of medicaments,including but not limited to medicaments useful in the treatment ofdepression, gastrointestinal side-effects of venlafaxine in a subjectundergoing treatment therewith, and irritable bowel syndrome.

In another embodiment, the present invention provides for the use ofmultiparticulate formulations of the invention in the preparation ofmedicaments for delivery to a pediatric or geriatric patient.

In other embodiments, the present invention provides for the use ofmultiparticulate formulations of the invention in the preparation ofdosing units, including but not limited to dosing units for oral,transdermal, or mucosal administration.

Also encompassed by the invention are pharmaceutical packs and kitscomprising a container, such as a foil package or other suitablecontainer, having a formulation of the invention in unit dosage form.

The following examples are illustrative of the invention.

EXAMPLE 1 PRODUCTION4-[2-DIMETHYLAMINO-1-(4-HYDROXY-PHENYL)-ETHYL]-PIPERIDIN-4-OL

The above-identified compound may be synthesized according to thefollowing scheme.

EXAMPLE 2 PRODUCTION4-[2-DIMETHYLAMINO-1-(4-HYDROXY-PHENYL)-ETHYL]-1-METHYL-PIPERIDIN-4-OL

This compound may be synthesized according to the following scheme.

EXAMPLE 3 SYNTHESIS4-[2-DIMETHYLAMINO-1-(4-HYDROXY-PHENYL)-ETHYL]-1-ETHYL-PIPERIDIN-4-OL

The title compound may be synthesized using the following scheme. Thehydrochloride salt can be made prior to the hydrogenation step.

EXAMPLE 4 PERMEABILITY ASSESSMENT OF COMPOUNDS OF INVENTION—HTS-24CACO-2 MODEL

The rate of drug transport through the caco-2 cells can be determined asthe Apparent Permeability Coefficient according to the followingformula:

$P_{app} = {\frac{\Delta\; Q}{\Delta\; T} \times \frac{Rv}{60 \cdot A \cdot C_{o}}{{cm} \cdot s^{- 1}}}$

ΔQ=Change in quantity

ΔT=Change in time (minutes)

C_(o)=Initial conc_(n) in the donor chamber (mM.cm⁻³)

A=Surface area of membrane (cm²)

60=Conversion factor to give cm.s⁻¹

Rv=volume of receiver compartment.

Transepithelial electrical resistance (TER) is calculated fromresistance measurements according to the following formula:TER=(R[cells+filter+medium])−(R[filter+medium])×cell area.

Apparent permeability rates are interpreted as follows. Apparentpermeability values which are equal to or greater than those observedfor metoprolol or propranolol during the same assay run are consideredto give a predicted fraction absorbed estimate of ≧90% (highpermeability classification). Apparent permeability values less thanmetoprolol or propranolol are considered to be ≦90% fa (moderatepermeability classification). Apparent permeability values of <10 nms⁻¹are considered to be ≦50% fa (low permeability classification). TERvalues of <120 ohms cm² indicate low monolayer integrity over the assayperiod.

A compound/metoprolol or propranolol ratio of ≧1 indicates a highpermeability compound. A compound/metoprolol or propranolol ratio of <1indicates a moderate to low permeability compound.

EXAMPLE 5 Pharmacology

Receptor assay binding studies are conducted in accordance withpublished and commercially available assays. These assays can beperformed as described in the following publications, as modified byNovascreen™ services. The receptor binding assays can include, e.g.,Adrenergic α-2A (human) binding assay [D. B. Bylund et al, J Pharmacol &Exp Ther, 245(2):600-607 (1988), with modifications; J A Totaro et al,Life Sciences, 44:459-467 (1989)]; dopamine transporter binding assay[Madras et al, Mol. Pharmacol., 36:518-524, with modifications, J JJavitch et al, Mol Pharmacol, 26:35-44 (1984)]; histamine H1 bindingassay [Chang, et al., J Neurochem, 32:1658-1663 (1979), withmodifications, J I Martinez-Mir, et al., Brain Res, 526:322-327 (1990);E E J Haaksma, et al, Pharmacol Ther, 47:73-104 (1990)]; imidazolinebinding assay [C M Brown et al, Brit. J Pharmacol, 99(4):803-809 (1990),with modifications], muscarinic M5 (human recombinant) binding assay [NJ Buckley et al, Mol Pharmacol, 35:469-476 (1989), with modifications];norepinephrine transporter (human recombinant) binding assay [R.Raisman, et al., Eur J Pharmacol, 78:345-351 (1982), with modification,S. Z. Raisman, et al, Eur J Pharmacol, 72:423 (1981)]; serotonintransporter (human) binding assay [R J D'Amato, et al, J Pharmacol & ExpTher, 242:364-371 (1987), with modifications; N L Brown et al, Eur JPharmacol, 123:161-165 (1986)]. The cellular/functional assays include,e.g., the norepinephrine transport (NET-T) human [A. Galli, et al, J ExpBiol, 198:2197-2212 (1995); and the serotonin transport (Human) assay[D'Amato et al, cited above and N L Brown et al, Eur J Pharmacol,123:161-165 (1986)]. The results are presented as percent (%) Inhibitionof the receptor. Published studies show that venlafaxine has 20%inhibition of Histamine H1 at 101M (Muth et al., Drug DevelopmentResearch 23:191-199 (1991)).

It is anticipated that the compounds of the invention will be selective.

The present invention is not to be limited in scope by the specificembodiments described herein. Various modifications to these embodimentswill be obvious to one of skill in the art from the description. Suchmodifications fall within the scope of the appended claims.

Patents, patent applications, publications, procedures and the like arecited throughout the application. These documents are incorporated byreference herein.

1. A compound of the structure:

wherein R²=H, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, CF₃, CN, halogen,OH, or a pharmaceutically acceptable salt thereof.
 2. The compound ofclaim 1, wherein R² is C₁-C₃ alkyl.
 3. The compound of claim 2, selectedfrom the group consisting of:4-[2-Dimethylamino-1-(4-hydroxy-phenyl)-ethyl]-1-methyl-piperidin-4-ol;4-[2-Dimethylamino-1-(4-hydroxy-phenyl)-ethyl]-1-ethyl-piperidin-4-ol;4-[2-Dimethylamino-1-(4-hydroxy-phenyl)-ethyl]-1-propyl-piperidin-4-ol;4-[2-Dimethylamino-1-(4-hydroxy-phenyl)-ethyl]-1-isopropyl-piperidin-4-ol-;or a pharmaceutically acceptable salt thereof.
 4. The compound accordingto claim 2, wherein R² is propyl or isopropyl.
 5. The compound accordingto claim 1, wherein R² is H.
 6. The compound according to claim 5,wherein the compound is4-[2-Dimethylamino-1-(4-hydroxy-phenyl)-ethyl]piperidin-4-ol, or apharmaceutically acceptable salt thereof.
 7. The compound according toclaim 1, wherein the pharmaceutically acceptable salt is selected from ahydrochloride, succinate or formate salt.
 8. A pharmaceuticalcomposition comprising a compound according to claim 1 andpharmaceutically acceptable carrier.
 9. The pharmaceutical compositionaccording to claim 8, comprising an oral dosage unit.
 10. Thepharmaceutical composition according to claim 8, wherein said oraldosage unit is a capsule or tablet.
 11. The pharmaceutical compositionaccording to claim 8, comprising an immediate release formulation. 12.The pharmaceutical composition according to claim 8, comprising asustained release formulation.
 13. The method of treating majordepressive disorder (MDD) comprising administering to a subject in needthereof, a therapeutically effective amount of a compound according toclaim 1.